G protein-coupled receptor (GPCR) gene variants and human genetic disease

作者：Miles D. Thompson, Maire E. Percy, David E.C. Cole, Daniel G. Bichet, Alexander S. Hauser, Caroline M. Gorvin · 发表于：Critical Reviews in Clinical Laboratory Sciences · 年份：2024 · DOI：10.1080/10408363.2023.2286606 · 被引用次数：28 · 研究领域：Receptor Mechanisms and Signaling、Regulation of Appetite and Obesity、Cellular transport and secretion

Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases.Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans.The spectrum of pathogenic and likely pathogenic variants includes loss of function variants that decrease receptor signaling on one extreme and gain of function that may result in biased signaling or constitutive activity, originally modeled on prototypical rhodopsin GPCR variants identified in retinitis pigmentosa, on the other.GPCR variants disrupt ligand binding, G protein coupling, accessory protein function, receptor desensitization and receptor recycling.Next generation sequencing has made it possible to identify variants of uncertain significance (VUS).We discuss variants in receptors known to result in disease and in silico strategies for disambiguation of VUS such as sorting intolerant from tolerant and polymorphism phenotyping.Modeling of variants has contributed to drug development and precision medicine, including drugs that target the melanocortin receptor in obesity and interventions that reverse loss of gonadotropin-releasing hormone receptor from the cell surface in idiopathic hypogonadotropic hypogonadism.Activating and inactivating variants of the calcium sensing receptor (CaSR) gene that are pathogenic in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia have en...